Process for the preparation of 2-(aminoethyl)phthalimidines



States atent G i ICC 3,445,476

Patented May 20, 1969 immiscible solvent, for example, ethyl acetate, ether, 3,445,476 chloroform, carbon tetrachloride and benzene; and the PROCESS FOR THE PREPAR T N extract evaporated to dryness to afford a 2-(2-aminoethyl) 2-(AMINOETHYDPHTHALEMHDINES phthalimidim (II).

Theodore S. Suikowski Nat-berth and Albert A. Mascitti, r

Norristown, Pa, assi griors to American Home Products 5 The tetrahydrolmldazolsomdolone eactants (I) em Corporation New York N Y a corporation of ployed in the process of the present invention are known Delaware compounds which are described and claimed in co-pend- No Drawing. Filed Mar. 14,1967,Ser.N0.622,919 s US patent app 2, fi on int. Cl. (307d 27/08, 31/42 June 2, 1966, entitled Benzodiazocines which is a con- U.S. Cl. 260-325 5 Claims 10 tinuation-in-part of U.S. patent application Ser. No. 444,-

050, filed on Mar. 30. 1965, and now abandoned.

The Z-(aminoethyl)phthalimidines which are prepared ABSTRACT OF THE DISCLOSURE by the new and novel process of the present invention are This invention is concerned with a process for the useful intermediates in the Preparation of hydrogenolysis of tetrahydroimidazoisoindolones to preethylfisoindolines which have demonstrated P pal-B 2-(2 amin0ethy1)phthalimidines which are f l cological activity as anti-depressants and anorexiants.

intermediates in the preparation of 2-(2-aminoethyl)iso- Thnse aminnethynisoindoiines fif described and indolines which are pharmacologically active as anti-declaimed in co'pending P pp i P N0. pressants and anorexiants On Mar. 14, entltled ISOmdOIeS,

Isoindolines and Related Compounds.

The following examples are given by way of illustra- This invention relates to a new and novel process for P f are to be construed as limitations of this the preparation of 2 (aminoethyl)phthalimidines which invention, varlations of which are possible without deare employed in intermediates in the preparation of the Parting from the 5C0?a and Spirit thereoftherapeutically efficacious 2-(Z-aminoethyl)isoindolines.

The new and novel process for the preparation of Examp 16 I these 2-(aminoethyl)phthalimidines is illustrated by the A mixture of g. of 9b-phenyl-l,2,3,9b-tetrahydrofollowing reaction scheme: 5H-imidazo[2,l-a]is0indol-5-one, 5 g. of 10% palladium 0 I! 2 I w Hydrogenolysjg n 3 H R N-CH CH NH wherein R is selected from the group consisting of hydroon charcoal and 200 ml. of acetic acid is shaken with gen, lower alkyl, phenyl, phen(lower)alkyl, monohal0- hydrogen at an initial pressure of 43 p.s.i. After the hyphenyl, dihalophenyl, mono(lower)alkylphenyl, di(lowdrogen uptake ceases (within one hour), the catalyst is er)alkylphenyl, trifluoromethylphenyl, mon0(lower)alkseparated by filtration and the filtrate is evaporated to oxyphenyl, di(lower)alkoxyphenyl, thienyl, pyridyl, furyl 5 dryness. The solid residue is dissolved in water and made and tetrahydr0-2-naphthy1; R is selected from the group basic with sodium hydroxide solution. The mixture is consisting of hydrogen, amino, lower alkyla i o, h extracted with ethyl acetate. After drying over magnesium tiiflnofofnethyi, lower aikyi and lower y; and sulfate, the ethyl acetate extract is evaporated in vacuo 3 is hydrogen when 2 and s are dissimilar and when to an oil. After cooling, there is obtained 2-(2-aminoeth- R and R are the same they are both selected from the yl) 3 pheny1phtha1imidine, C. The hydrochlo group consisting of hydrogen, halogen, lower alkyl and ride of Lam-110mb 1 he 1 hth lower alkoxy. The hydrogenolysis reaction is effected by by reactign z g i 2;}; 263 formid contacting a tetrahydroimidazoisoindolone (I) with a palladium charcoal catalyst, in an appropriate solvent, e.g. 3 52 fi g g i g wlth 9b (p'.chiomph6n' acetic acid, under a positive hydrogen atmosphere with 55 y ftetra H azoizl ailsomdol stirring until the hydrogen uptake ceases. Preferably this f 'g reaction is conducted with a 10% palladium on charcoal ynphthahmldme hydrochloride 305 catalyst in acetic acid under about 45 p.s.i. of hydrogen pressure. By palladium charcoal catalyst as employed Example 11 herein is meant a catalyst consisting of about two percent to about ten percent palladium on charcoal. The A ture of 12.5 g. of 9b-(p-methoxyphenyl)-1,2,3, term positive hydrogen atmosphere is defined to mean y ZO[ ,1-a]isoindol-S-one, 5 g. of a hydrogen atmosphere under a positive pressure of about 5% palladium on charcoal and 100 m1. of acetic acid is 15 psi. to about 75 p.s.i. shaken with hydrogen at an initial pressure of 75 p.s.i.

When the hydrogenolysis reaction is complete, the After the hydrogen uptake ceases, the catalyst is separated product (II) is separated by procedures well known in by filtration and the filtrate evaporated to dryness. The the art, for example, the catalyst is removed by filtration solid residue is dissolved in water, made basic with or decantation; the filtrate evaporated to dryness; the potassium hydroxide solution and extracted with chlororesidue dissolved in water, basified with a base, e.g. soform. After drying over magnesium sulfate, the extract dium hydroxide, potassium hydroxide, sodium bicarbonis evaporated to afford 2-(Z-aminoethyl)-3-(p-methoxyate and potassium bicarbonate; extracted with a waterphenyl)phthalimidine.

In a similar manner, 8-amino-9b-phenyl-1,2,9b-tetrahydro-SH-imidazo[2,l-a1isoindol-5-one is converted to 5 -amino-2- (Z-aminoethyl) -3-phenylphthalimidine.

Example III The procedure of Examples I and II is repeated on the hereinafter listed tetrahydroimidazoisoindolones to produce the following 2-(Z-aminoethyl)phthalimidines:

Tetrahydroimidazoisoindolones 2-(2-aminoethyl) phthalimidines 2-(2-aminoethyl)-3-(p-fluorophenyDphthalimidine.

2-(2-aminoethyl)-3-(2-thienyl) phthalimidine.

me. 2-(2-aminoethyl)-6-methyl-3- phenylphthalimidine.

2-(2-aminoethyl)-6-methoxy-3- phenylphthalimidme.

dine. 2-(2-aminoetl1yl)-7-chloro-3- phenylphthalimidine.

[2,1-a1isoindol-5-one. phthalimldine. Qb-ethyl-l,2,3,9b-tet;rahydro-5H- 2-(2-aminoe tl' y1)-3-ethylimidazo[2,1-a1isoindoL5-one. phthalimidine.

2-(2-aminoethyl)-5-bromo-3 ((ip-ethoxyphenyl)phthalimi- 2-(2-aminoethy1) cmeth l-stetrahydro-5H-imidazo[2,1-a] (p-tolyl) phthalimidine.

isoindol-E-one. 7,8-dichloro-9b-phenyl-1,2,3,9b- Z-(Z-aminoethyl){6,6 dichlorotetrahydro-SH-imidazolZ,l-a] 3phenylpht.halimidme.

isomdol-S-one. 7,8-dibromo-9b-(2-thienyl)- 1,2,3,9b-tetrahydro-5H- imidazo [2,1-a]isindol-5one. 9b-phenethy1-1,2,3,9b-tetrahydro-SH-imidazo[2,1-a11s0- indul--one.

2-(2-aminoethyD-5.fi-dibromo- 3-(2-thienyl)phthalimidine.

2-(2-aminoethyl)-3-phenethylphthalimidine.

Example IV A mixture of g. of 9-b- (2,4-dimethoxyphenyl)-1,2, 3,9b tetrahydro 5H imidazo[2,I-aJisoindol-S-on, 25 g. of 2% palladium on charcoal and 200 ml. of acetic acid is shaken with hydrogen at an initial pressure of 15 p.s.i. After the hydrogen uptake is complete, the catalyst is separated by filtnation and the filtrate evaporated to dryness. The solid residue is dissolved in water, made basic with sodium bicarbonate solution and the mixture is extracted with benzene. After drying over magnesium sulfate, the extract is evaporated in vacuo to afford 2- (Z-aminoethyl) -3- (2,4-dimethoxyphenyl phthalimidine.

Similarly, S-methylamino 1,2,3,9b tetrahydro 9bphenyl-SH-imidazo[2,1-a]isoindol-5-one is subjected to hydrogenolysis to atford 2-(Z-aminophenyl)-5-methylamino-3-phenylphthalimidine.

Example V A mixture of g. of 9b-(3,4-dichlorophenyl)-1,2,3, 9b-tetra-hydro-SH-imidazo[2,1,-a]isoindol-5-one, 10 g. of 10% palladium on charcoal and 400 ml. of acetic acid is shaken with hydrogen at an initial pressure of 50 p.s.i. After the hydrogen uptake ceases, the catalyst is separated by filtration and the filtrate evaporated to dryness. The solid residue is dissolved in water and made basic with potassium bicarbonate solution. The mixture is ex tracted with ethyl acetate. After drying over magnesium sulfate, the extract is evaporated in vacuo to afford 2-(2- aminoethyl) -3 (-3,4-dichlorophenyl phthalimidine.

4 Example VI A mixture of 25 g. of 9b-(2,4-di-bromophenyl)-1,2,3, 9b-tetrahydro-5H-imidazo[2,1-a1isoindol-5-one, 5 g. of 10% palladium on charcoal and 200 ml. of acetic acid is shaken with hydrogen at an initial pressure of 50 p.s.i. After the hydrogen uptake ceases (Within one hour), the catalyst is separated by filtration and the filtration evaporated to dryness. The solid residue is dissolved in water and made basic with sodium hydroxide solution. The mixture is extracted with chloroform. After drying over magnesium sulfate, the extract is evaporated in vacuo to afford 24(2-aminoethy1)-3=(2,4-dibromophenyl) phthalimidine.

In a similar manner, 9b-(m-lluorophenyl)-1,2,3,9btetrahydro 5H-imidazo[2,1-a]isoindol 5 one; 9b-(pbromophenyl) l,2,3,9'b-tetrahydro 5H-imidazo[2,1-a] isoindol-S-one; and 9b-(5,6,7,8-tetrahydro-2-naphthyl)- 1,2,3,9b-tetrahydro-SH-imidazo[2,1-a]isoindol-5-one are respectively converted to 2-(2-arninoethyl)-3-(rn-fluorophenyl)phthalimidine; 2 (2-amino-ethyl)-3-(p brom0- phenyl)phthalimidine; and Z-(Z-aminoethyl)-3-(5,6,7,8- tetrahydro-Z-naphthyl)phthalimidine.

Example VII A mixture of 75 g. of 9b-(p-ethylphenyl)-l,2,3,9b-tetrahydro-SH-imidazo[2,1-a]isoindol-5-one, 15 g. of 10% palladium on charcoal and 600 ml. of acetic acid is shaken with hydrogen at an initial pressure of 45 p.s.i. After the hydrogen uptake ceases, the catalyst is separated by filtration and the filtrate evaporated to dryness. The solid residue is dissolved in water and made basic with sodium hydroxide solution. The mixture is extracted with ethyl acetate. After drying over magnesium sulfate, the extract is evaporated in vacuo to afiord 2-(2-aminoethyl)-3-(pethylphenyl) phthalimidine.

In a similar manner, 1,2,3,9b-tetrahydro-7,S-dimethyl- 9b-phenyl-5H-imidazo(2,1-a)isoindol-S-one is converted to 2-(2-aminoethyl)-5,6-dimethyl-3-phenylphthalimidine.

Example VIII A mixture of 25 g. of 9b-benzyl-1,2,3,9b-tetrahydro-5H- imidazo[2,1-a1isoindol-5-one, 5 g. of 10% palladium on charcoal and 200 ml. of acetic acid is shaken with hydrogen at an initial pressure of 43 p.s.i. After the hydrogen uptake ceases (within one hour), the catalyst is separated by filtration and the filtrate evaporated to dryness. The solid residue is dissolved in water and made basic with sodium hydroxide solution. The mixture is extracted with ethyl acetate. After drying over magnesium sulfate, the extract is evaporated in vacuo and the residue reacted with acetic acid to afford 2-(Z-aminoethyl)-3-benzylphthalimidine acetate, M.P. 15 6-157 C.

What is claimed is:

1. A process for the preparation of compounds having the formula:

N-CHQCHENHE 3 wherein R is selected from the group consisting of hydrogen, lower alkyl, phenyl, phen(lower)alkyl, monohalophenyl, dihalophenyl, mono(lower)alkylphenyl, di(lower)alkylphenyl, trifluoromethylphenyl, mono (lower)alkoxyphenyl, di(lower)alkoxyphenyl, thienyl, pyridyl, furyl and tetrahydro-Z-naphthyl; R is selected from the group consisting of hydrogen, amino, lower alkylamino, halogen, trifiuoromethyl, lower alkyl and lower alkoxy; and R is hydrogen when R and R are dissimilar and when R and R are the same they are both selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, which comprises contacting a tetrahydroimidazoisoindolone of the formula:

wherein R R and R are defined as above, with a palladium charcoal catalyst, consisting of about two to about ten percent palladium on charcoal, in acetic acid, under a positive hydrogen atmosphere of from about p.s.i. to about 75 p.s.i.

2. A process as described in claim 1 wherein the palladium charcoal catalyst consists of ten percent palladium on charcoal and the positive hydrogen atmosphere is 45 p.s.i.

3. A process as described in claim 1 for the preparation of 2-(2-aminoethyl)-3-phenylphthalimidine which comprises contacting 9b-phcnyl-1,2,3,9b-tetrahydro-5H-imidazo-[2,l-a]isoindol-5-one with a ten percent palladium on charcoal catalyst, in acetic acid, under a positive hydrogen atmosphere of 45 p.s.i.

4. A process as described in claim 1 for the preparation of 2-(Z-aminoethyl)-3-(p-chlorophenyl)phthalimidine hydrochloride which comprises contacting 9b-(p-chlorophenyl)-1,2,3,9b-tetrahydro 5H imidazo[2,1 a] isoindol 5- one with a ten percent palladium on charcoal catalyst, in acetic acid, under a positive hydrogen atmosphere of p.s.1.

5. A process as described in claim 1 for the preparation of 2-(Z-aminoethyl)-3-benzylphthalimidine acetate which comprises contacting 9b-benzyl-l,2,3,9b-tetrahydro-5H- imidazo[2,l-a]isoindol-5-one with a ten percent palladium on charcoal catalyst, in acetic acid, under a positive hydrogen atmosphere of 45 p.s.i.

References Cited UNITED STATES PATENTS 3,334,113 8/1967 Houlihan 260--325 XR ALEX MAZEL, Primaiy Examiner.

J. A. NARCAVAGE, Assistant Examiner.

U.S. Cl. X.R. 

